Top

02-15-2018 | Nephropathy | Review | Article

Diabetic Kidney Disease: Is There a Role for Glycemic Variability?

Journal: Current Diabetes Reports

Authors: Savitha Subramanian, Irl B. Hirsch

Abstract

Purpose of Review

Diabetes is the leading cause of kidney disease globally. Diabetic kidney disease (DKD) is a heterogeneous disorder manifested as albuminuria and/or decreasing GFR. Hyperglycemic burden is the major contributor to the development of DKD. In this article, we review the evidence for the contribution of glycemic variability and the pitfalls associated with use of hemoglobin A1c (A1C), the gold standard for assessment of glucose control, in the setting of DKD.

Recent Findings

Glycemic variability, characterized by swings in blood glucose levels, can result in generation of mitochondrial reactive oxygen species, a putative inciting factor for hyperglycemia-induced alterations in intracellular metabolic pathways. While there is indirect evidence supporting the role of glycemic variability in the pathogenesis of DKD, definitive data are lacking. A1C has many limitations and is a particularly suboptimal measure in patients with kidney disease, because its accuracy is compromised by variables affecting RBC survival and other factors. Continuous glucose monitoring (CGM) technology has the potential to enable us to use glucose as a more important clinical tool, for a more definitive understanding of glucose variability and its role in DKD.

Summary

Glycemic variability may be a factor in the development of DKD, but definitive evidence is lacking. Currently, all available glycemic biomarkers, including A1C, have limitations and in the setting of DKD and should be used cautiously. Emerging data suggest that personal and professional CGM will play an important role in managing diabetes in patients with DKD, where risk of hypoglycemia is high.

Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA. 2016;316(6):602–10. https://doi.org/10.1001/jama.2016.10924.CrossRefPubMedPubMedCentral

de Boer IH. A new chapter for diabetic kidney disease. N Engl J Med. 2017;377(9):885–7.CrossRefPubMed

Mayer-Davis EJ, Lawrence JM, Dabelea D, Divers J, Isom S, Dolan L, et al. Incidence trends of type 1 and type 2 diabetes among youths, 2002-2012. N Engl J Med. 2017;376(15):1419–29. https://doi.org/10.1056/NEJMoa1610187.CrossRefPubMedPubMedCentral

Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314(10):1021–9. https://doi.org/10.1001/jama.2015.10029.CrossRefPubMed

Reidy K, Kang HM, Hostetter T, Susztak K. Molecular mechanisms of diabetic kidney disease. J Clin Invest. 2014;124(6):2333–40. https://doi.org/10.1172/JCI72271.CrossRefPubMedPubMedCentral

• Thomas MC, Brownlee M, Susztak K, Sharma K, Jandeleit-Dahm KA, Zoungas S, et al. Diabetic kidney disease. Nat Rev Dis Primers. 2015;1:15018. A comprehensive review on diabetic kidney disease.CrossRefPubMed

Pirart J. Glycaemic control and development of diabetic nephropathy. Acta Endocrinol Suppl (Copenh). 1981;242:41–2.

Diabetes C, Complications Trial Research G, Nathan DM, Genuth S, Lachin J, Cleary P, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–86. https://doi.org/10.1056/NEJM199309303291401.CrossRef

Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93(1):137–88.CrossRefPubMed

10.

Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood). 2008;233(1):4–11. https://doi.org/10.3181/0705-MR-134.CrossRef

11.

Brasacchio D, Okabe J, Tikellis C, Balcerczyk A, George P, Baker EK, et al. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes. 2009;58(5):1229–36. https://doi.org/10.2337/db08-1666.CrossRefPubMedPubMedCentral

12.

Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615–25. https://doi.org/10.2337/diabetes.54.6.1615.CrossRefPubMed

13.

Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20. https://doi.org/10.1038/414813a.CrossRefPubMed

14.

Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 2000;49(11):1939–45. https://doi.org/10.2337/diabetes.49.11.1939.CrossRefPubMed

15.

Susztak K, Raff AC, Schiffer M, Bottinger EP. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006;55(1):225–33. https://doi.org/10.2337/diabetes.55.01.06.db05-0894.CrossRefPubMed

16.

Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008;57(5):1349–54. https://doi.org/10.2337/db08-0063.CrossRefPubMed

17.

Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295(14):1681–7. https://doi.org/10.1001/jama.295.14.1681.CrossRefPubMed

18.

Wentholt IM, Kulik W, Michels RP, Hoekstra JB, DeVries JH. Glucose fluctuations and activation of oxidative stress in patients with type 1 diabetes. Diabetologia. 2008;51(1):183–90. https://doi.org/10.1007/s00125-007-0842-6.CrossRefPubMed

19.

Waden J, Forsblom C, Thorn LM, Gordin D, Saraheimo M, Groop PH, et al. A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes. Diabetes. 2009;58(11):2649–55. https://doi.org/10.2337/db09-0693.CrossRefPubMedPubMedCentral

20.

Lin CC, Chen CC, Chen FN, Li CI, Liu CS, Lin WY, et al. Risks of diabetic nephropathy with variation in hemoglobin A1c and fasting plasma glucose. Am J Med. 2013;126(11):1017 e1–10.CrossRef

21.

Sugawara A, Kawai K, Motohashi S, Saito K, Kodama S, Yachi Y, et al. HbA(1c) variability and the development of microalbuminuria in type 2 diabetes: Tsukuba Kawai Diabetes Registry 2. Diabetologia. 2012;55(8):2128–31. https://doi.org/10.1007/s00125-012-2572-7.CrossRefPubMed

22.

Penno G, Solini A, Bonora E, Fondelli C, Orsi E, Zerbini G, et al. HbA1c variability as an independent correlate of nephropathy, but not retinopathy, in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Diabetes Care. 2013;36(8):2301–10. https://doi.org/10.2337/dc12-2264.CrossRefPubMedPubMedCentral

23.

Downie E, Craig ME, Hing S, Cusumano J, Chan AK, Donaghue KC. Continued reduction in the prevalence of retinopathy in adolescents with type 1 diabetes: role of insulin therapy and glycemic control. Diabetes Care. 2011;34(11):2368–73. https://doi.org/10.2337/dc11-0102.CrossRefPubMedPubMedCentral

24.

Kilpatrick ES, Rigby AS, Atkin SL. The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care. 2006;29(7):1486–90. https://doi.org/10.2337/dc06-0293.CrossRefPubMed

25.

Kilpatrick ES, Rigby AS, Atkin SL. A1C variability and the risk of microvascular complications in type 1 diabetes: data from the diabetes control and complications trial. Diabetes Care. 2008;31(11):2198–202. https://doi.org/10.2337/dc08-0864.CrossRefPubMedPubMedCentral

26.

Kilpatrick ES, Rigby AS, Atkin SL. Effect of glucose variability on the long-term risk of microvascular complications in type 1 diabetes. Diabetes Care. 2009;32(10):1901–3. https://doi.org/10.2337/dc09-0109.CrossRefPubMedPubMedCentral

27.

Lachin JM, Bebu I, Bergenstal RM, Pop-Busui R, Service FJ, Zinman B, et al. Association of glycemic variability in type 1 diabetes with progression of microvascular outcomes in the diabetes control and complications trial. Diabetes Care. 2017;40(6):777–83. https://doi.org/10.2337/dc16-2426.CrossRefPubMed

28.

Mirani M, Berra C, Finazzi S, Calvetta A, Radaelli MG, Favareto F, et al. Inter-day glycemic variability assessed by continuous glucose monitoring in insulin-treated type 2 diabetes patients on hemodialysis. Diabetes Technol Ther. 2010;12(10):749–53. https://doi.org/10.1089/dia.2010.0052.CrossRefPubMed

29.

Lung TW, Petrie D, Herman WH, Palmer AJ, Svensson AM, Eliasson B, et al. Severe hypoglycemia and mortality after cardiovascular events for type 1 diabetic patients in Sweden. Diabetes Care. 2014;37(11):2974–81. https://doi.org/10.2337/dc14-0405.CrossRefPubMed

30.

Lind M, Svensson AM, Kosiborod M, Gudbjornsdottir S, Pivodic A, Wedel H, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371(21):1972–82. https://doi.org/10.1056/NEJMoa1408214.CrossRefPubMed

31.

Robinson RT, Harris ND, Ireland RH, Macdonald IA, Heller SR. Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with type 1 diabetes. Diabetologia. 2004;47(2):312–5. https://doi.org/10.1007/s00125-003-1292-4.CrossRefPubMed

32.

Frier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular risks. Diabetes Care. 2011;34(Suppl 2):S132–7. https://doi.org/10.2337/dc11-s220.CrossRefPubMedPubMedCentral

33.

Ceriello A, Novials A, Ortega E, La Sala L, Pujadas G, Testa R, et al. Evidence that hyperglycemia after recovery from hypoglycemia worsens endothelial function and increases oxidative stress and inflammation in healthy control subjects and subjects with type 1 diabetes. Diabetes. 2012;61(11):2993–7. https://doi.org/10.2337/db12-0224.CrossRefPubMedPubMedCentral

34.

Abe M, Kalantar-Zadeh K. Haemodialysis-induced hypoglycaemia and glycaemic disarrays. Nat Rev Nephrol. 2015;11(5):302–13. https://doi.org/10.1038/nrneph.2015.38.CrossRefPubMed

35.

Raimann JG, Kruse A, Thijssen S, Kuntsevich V, Dabel P, Bachar M, et al. Metabolic effects of dialyzate glucose in chronic hemodialysis: results from a prospective, randomized crossover trial. Nephrol Dial Transplant. 2012;27(4):1559–68. https://doi.org/10.1093/ndt/gfr520.CrossRefPubMed

36.

Kazempour-Ardebili S, Lecamwasam VL, Dassanyake T, Frankel AH, Tam FW, Dornhorst A, et al. Assessing glycemic control in maintenance hemodialysis patients with type 2 diabetes. Diabetes Care. 2009;32(7):1137–42. https://doi.org/10.2337/dc08-1688.CrossRefPubMedPubMedCentral

37.

Ricks J, Molnar MZ, Kovesdy CP, Shah A, Nissenson AR, Williams M, et al. Glycemic control and cardiovascular mortality in hemodialysis patients with diabetes: a 6-year cohort study. Diabetes. 2012;61(3):708–15. https://doi.org/10.2337/db11-1015.CrossRefPubMedPubMedCentral

38.

Chu YW, Lin HM, Wang JJ, Weng SF, Lin CC, Chien CC. Epidemiology and outcomes of hypoglycemia in patients with advanced diabetic kidney disease on dialysis: a national cohort study. PLoS One. 2017;12(3):e0174601. https://doi.org/10.1371/journal.pone.0174601.CrossRefPubMedPubMedCentral

39.

American Diabetes A. 6. Glycemic Targets. Diabetes Care. 2017;40(Suppl 1):S48–56. https://doi.org/10.2337/dc17-S009.CrossRef

40.

Bergenstal RM, Gal RL, Connor CG, Gubitosi-Klug R, Kruger D, Olson BA, et al. Racial differences in the relationship of glucose concentrations and hemoglobin A1c levels. Ann Intern Med. 2017;167(2):95–102. https://doi.org/10.7326/M16-2596.CrossRefPubMed

41.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–53.CrossRef

42.

Ansari A, Thomas S, Goldsmith D. Assessing glycemic control in patients with diabetes and end-stage renal failure. Am J Kidney Dis. 2003;41(3):523–31. https://doi.org/10.1053/ajkd.2003.50114.CrossRefPubMed

43.

Sharif A, Baboolal K. Diagnostic application of the A(1c) assay in renal disease. J Am Soc Nephrol. 2010;21(3):383–5.CrossRefPubMedPubMedCentral

44.

Herman WH, Ma Y, Uwaifo G, Haffner S, Kahn SE, Horton ES, et al. Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Prevention Program. Diabetes Care. 2007;30(10):2453–7. https://doi.org/10.2337/dc06-2003.CrossRefPubMedPubMedCentral

45.

Herman WH. Do race and ethnicity impact hemoglobin A1c independent of glycemia? J Diabetes Sci Technol. 2009;3(4):656–60. https://doi.org/10.1177/193229680900300406.CrossRefPubMedPubMedCentral

46.

Wright LA, Hirsch IB. Metrics beyond hemoglobin A1C in diabetes management: time in range, hypoglycemia, and other parameters. Diabetes Technol Ther. 2017;19(S2):S16–26. https://doi.org/10.1089/dia.2017.0029.CrossRefPubMed

47.

Vos FE, Schollum JB, Coulter CV, Doyle TC, Duffull SB, Walker RJ. Red blood cell survival in long-term dialysis patients. Am J Kidney Dis. 2011;58(4):591–8. https://doi.org/10.1053/j.ajkd.2011.03.031.CrossRefPubMed

48.

Nakao T, Matsumoto H, Okada T, Han M, Hidaka H, Yoshino M, et al. Influence of erythropoietin treatment on hemoglobin A1c levels in patients with chronic renal failure on hemodialysis. Intern Med. 1998;37(10):826–30. https://doi.org/10.2169/internalmedicine.37.826.CrossRefPubMed

49.

Uzu T, Hatta T, Deji N, Izumiya T, Ueda H, Miyazawa I, et al. Target for glycemic control in type 2 diabetic patients on hemodialysis: effects of anemia and erythropoietin injection on hemoglobin A(1c). Ther Apher Dial. 2009;13(2):89–94. https://doi.org/10.1111/j.1744-9987.2009.00661.x.CrossRefPubMed

50.

Spencer DH, Grossman BJ, Scott MG. Red cell transfusion decreases hemoglobin A1c in patients with diabetes. Clin Chem. 2011;57(2):344–6. https://doi.org/10.1373/clinchem.2010.157321.CrossRefPubMed

51.

Inaba M, Okuno S, Kumeda Y, Yamada S, Imanishi Y, Tabata T, et al. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol. 2007;18(3):896–903. https://doi.org/10.1681/ASN.2006070772.CrossRefPubMed

52.

Batacchi ZAI, Zelnick L, Robinson-Cohen C, Healy J, Henry C, Robinson N, et al. Accuracy of glycosylated hemoglobin in chronic kidney disease. Diabetes. 2017;67(Suppl 1):LB7.

53.

•• Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading. J Gen Intern Med. 2014;29(2):388–94. A detailed review of inaccuracies in A1C measurements.CrossRefPubMed

54.

Selvin E, Rawlings AM, Grams M, Klein R, Steffes M, Coresh J. Association of 1,5-anhydroglucitol with diabetes and microvascular conditions. Clin Chem. 2014;60(11):1409–18. https://doi.org/10.1373/clinchem.2014.229427.CrossRefPubMedPubMedCentral

55.

Hirsch IB. Professional flash continuous glucose monitoring as a supplement to A1C in primary care. Postgrad Med. 2017;1–10.

56.

Lacy ME, Wellenius GA, Sumner AE, Correa A, Carnethon MR, Liem RI, et al. Association of sickle cell trait with hemoglobin A1c in African Americans. JAMA. 2017;317(5):507–15. https://doi.org/10.1001/jama.2016.21035.CrossRefPubMedPubMedCentral

57.

Lind M, Polonsky W, Hirsch IB, Heise T, Bolinder J, Dahlqvist S, et al. Continuous glucose monitoring vs conventional therapy for glycemic control in adults with type 1 diabetes treated with multiple daily insulin injections: the GOLD randomized clinical trial. JAMA. 2017;317(4):379–87. https://doi.org/10.1001/jama.2016.19976.CrossRefPubMed

58.

Beck RW, Riddlesworth TD, Ruedy K, Ahmann A, Haller S, Kruger D, et al. Continuous glucose monitoring versus usual care in patients with type 2 diabetes receiving multiple daily insulin injections: a randomized trial. Ann Intern Med. 2017;167(6):365–74. https://doi.org/10.7326/M16-2855.CrossRefPubMed

59.

Carlson AL, Mullen DM, Bergenstal RM. Clinical use of continuous glucose monitoring in adults with type 2 diabetes. Diabetes Technol Ther. 2017;19(S2):S4–S11. https://doi.org/10.1089/dia.2017.0024.CrossRefPubMed

60.

Joubert M, Fourmy C, Henri P, Ficheux M, Lobbedez T, Reznik Y. Effectiveness of continuous glucose monitoring in dialysis patients with diabetes: the DIALYDIAB pilot study. Diabetes Res Clin Pract. 2015;107(3):348–54. https://doi.org/10.1016/j.diabres.2015.01.026.CrossRefPubMed

61.

Yeoh EC, Lim BK, Fun S, Tong J, Yeoh LY, Sum CF, et al. Efficacy of self-monitoring of blood glucose versus retrospective continuous glucose monitoring in improving glycaemic control in diabetic kidney disease patients. Nephrology (Carlton). 2016. https://doi.org/10.1111/nep.12978.

62.

•• Hirsch IB, Verderese CA. Professional continuous flash glucose monitoring with ambulatory glucose profile reporting to supplement A1c: rationale and practical implementation. Endocr Pract. 2017. This article explains flash glucose monitoring, its clinical use, data interpretation, and benefits for use in patients with type 1 and type 2 diabetes.

63.

Bolinder J, Antuna R, Geelhoed-Duijvestijn P, Kroger J, Weitgasser R. Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes: a multicentre, non-masked, randomised controlled trial. Lancet. 2016;388(10057):2254–63. https://doi.org/10.1016/S0140-6736(16)31535-5.CrossRefPubMed

64.

Haak T, Hanaire H, Ajjan R, Hermanns N, Riveline JP, Rayman G. Use of flash glucose-sensing technology for 12 months as a replacement for blood glucose monitoring in insulin-treated type 2 diabetes. Diabetes Ther. 2017;8(3):573–86. https://doi.org/10.1007/s13300-017-0255-6.CrossRefPubMedPubMedCentral

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform.

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »